Large gaps remain in our understanding of the molecular mechanisms that activate the growth of ovarian primordial follicles, the first step of a process (follicular maturation) that culminates in egg release (ovulation). We will systematically dissect the key signalling pathway that requires the forkhead transcription factor FoxO3 to regulate the delicate balance between primordial follicle preservation and activation. Our goals are to: 1) exploit genetic approaches to confirm the importance of key genes encoding pathway components and to uncover their specific roles in primordial follicle activation;2) identify and validate physiologic targets of FoxO3 by comparing transcriptional profiles of ovaries derived from FoxO3-deficient and wild-type control females;3) characterize changing expression patterns, subcellular localization, and activation status of pathway components in primordial and early growing follicles, using a combination of antibody probes, pharmacologic agents, and in vitro culture, thereby revealing essential details of how this pathway regulates primordial follicle activation;4) screen for genetic variants or mutations of the FOXO3A gene--the only known potent suppressor of primordial follicle activation-in women with premature ovarian failure (a condition associated with the depletion of primordial follicles early in life), thereby testing the hypothesis that an increased rate of follicle activation is one cause of premature ovarian failure. An improved understanding of this pathway will lead to insights into the biological and genetic basis of female infertility, create significant opportunities to develop predictive genetic tests for hereditary forms of female infertility, and may some day lead to the development of improved contraceptives that preserve the primordial follicle pool. These studies could also lead directly to prognostic tests to identify women predisposed to develop premature ovarian failure.